DEEP VEIN

THROMBOSIS
Jane Chun-wen Teng D.O.
11/14/12

Overview of the Causes for Deep Vein

Thrombosis
The most common presentations of venous thrombosis are

deep vein thrombosis (DVT) of the lower extremity and

pulmonary embolism.
Distal (calf) vein thrombosis, in which thrombi remain confined

to the deep calf veins

Proximal vein thrombosis, in which thrombosis involves the
popliteal, femoral, or iliac veins
Proximal vein thrombosis is of greater importance clinically,

since it is more commonly associated with the development of

pulmonary emboli.
The causes of venous thrombosis can be divided into two

groups: hereditary and acquired.

Virchows Triad
VIRCHOW'S TRIAD A major theory delineating the

pathogenesis of venous thromboembolism (VTE), often

called Virchow's triad
Alterations in blood flow (ie, stasis)
Vascular endothelial injury
Alterations in the constituents of the blood (ie, inherited or

acquired hypercoagulable state)

Epidemiology
Among 1102 acutely ill, immobilized general medical
patients enrolled in the MEDENOX study, multiple logistic
regression analysis found the following factors to be
significantly and independently associated with an
increased risk for VTE, most of which were asymptomatic
and diagnosed by venography of both lower extremities
Presence of an acute infectious disease
Age >75 years
Cancer
History of prior VTE

Risk Factors for DVT

History of immobilization or prolonged hospitalization/bed

rest
Recent surgery
Obesity
Prior episode(s) of venous thromboembolism
Lower extremity trauma
Malignancy
Use of oral contraceptives or hormone replacement
therapy
Pregnancy or postpartum status
Stroke

History of DVT
History Classic symptoms of DVT include swelling,

pain, and erythema of the involved extremity. There is

not necessarily a correlation between the location of
symptoms and the site of thrombosis. Symptoms in the
calf alone are often the presenting manifestation of
significant proximal vein involvement, while some patients
with whole leg symptoms are found to have isolated calf
vein DVT.
A complete thrombosis history includes the age of onset,
location of prior thromboses, and results of objective
diagnostic studies documenting thrombotic episodes in
the patient.

History of DVT
The patient should be carefully questioned concerning recent

potential precipitating conditions prior to the time of

thrombosis, such as surgical procedures, hospitalization,
trauma, pregnancy, heart failure, and immobility.
Women should be carefully questioned regarding use of oral

contraceptives or hormone replacement therapy as well as

their obstetric history. The presence of recurrent fetal loss in
the second or third trimester suggests the possible presence of
an inherited thrombophilia or antiphospholipid antibodies.
In addition to events proximate to the time of thrombosis,

patients should also be questioned about previous exposure

and outcome in situations that predispose to thrombosis, such
as pregnancy, cesarean section, and surgery.

History of DVT
Questions should include the presence of significant disorders,

such as collagen-vascular disease, myeloproliferative disease,

atherosclerotic disease, or nephrotic syndrome and about the
use of drugs which can induce antiphospholipid antibodies
such as hydralazine, procainamide, and phenothiazine.
The patient should also be questioned about a past history of

cancer, and the results, if any, of regular screening

examinations for cancer since recurrent thrombosis in spite of
therapeutic anticoagulation with oral anticoagulants is more
frequent in patients with VTE in association with active cancer
or an occult neoplasm.
Other findings that may suggest an underlying malignancy are

constitutional symptoms such as loss of appetite, weight loss,

fatigue, pain, hematochezia, hemoptysis, and hematuria

Family History of DVT

A positive family history of VTE is particularly important,

since a well documented history of VTE in one or more

first-degree relatives under age 50 suggests the presence
of a hereditary defect and/or an increased susceptibility
for venous thromboembolic disease.
This was most conclusively shown in a population-based
study of the incidence of VTE according to the presence
or absence of VTE in a sibling.
Standard incidence ratios for VTE were 2.27, 51.9, and
53.7 for patients with one, two, or three or more affected
siblings, respectively.

Special Clinical Settings

There a number of clinical settings which may suggest the

presence of a specific risk factor for DVT. As examples:

Recurrent unprovoked DVT in a young patient (age <50) may

suggest either the presence of an inherited hypercoagulable

state or a congenital anomaly of the inferior vena cava.
Recurrent left lower extremity DVT of the left lower extremity

may indicate the presence of the May-Thurner syndrome with

thrombosis of the left iliac vein due to compression of this vein
between the overlying right iliac artery and the vertebral
column.

Physical Exam
Physical examination may reveal a palpable cord

(reflecting a thrombosed vein), calf or thigh pain, unilateral

edema or swelling with a difference in calf diameters,
warmth, tenderness, erythema, and/or superficial venous
dilation.
In the general physical examination, special attention

should be directed to the vascular system, extremities

(eg, looking for signs of superficial or deep vein
thrombosis), chest, heart, abdominal organs, and skin
(eg, skin necrosis, livedo reticularis).

Livedo Reticularis

Physical Exam
There may be pain and tenderness in the thigh along the

course of the major veins. Tenderness on deep palpation

of the calf muscles is suggestive, but not diagnostic.
Homans sign is also unreliable.
However, each of the above signs and symptoms is

nonspecific and has low accuracy for making the

diagnosis of DVT. A 2005 meta-analysis of diagnostic
cohort studies of patients with suspected DVT concluded
the following concerning these physical findings

Physical Exam
Only a difference in calf diameters (likelihood ratio, LR 1.8;

95% CI 1.5-2.2) was of potential value for ruling in DVT.

Only absence of calf swelling (LR 0.67; 95% CI 0.58-0.78) and
absence of a difference in calf diameters (LR 0.57; 95% CI
0.44-0.72) were of potential value for ruling out DVT.
Individual clinical features are poorly predictive of DVT when
not combined in a formal prediction rule (e.g. Wells score)
Accordingly, further diagnostic testing is required to confirm or

exclude the diagnosis of DVT

Physical Exam
Venous thromboembolism may also be associated with

other clinical disorders such as heart failure and the

myeloproliferative neoplasms. The presence or absence
of relevant physical exam findings (e.g., splenomegaly in
polycythemia vera) should be ascertained.
The physical examination may also reveal signs of

hepatic vein thrombosis (Budd-Chiari syndrome), such as

ascites and hepatomegaly, or edema due to the nephrotic
syndrome. The hypercoagulable state associated with the
nephrotic syndrome may manifest as renal vein
thrombosis, which is usually asymptomatic unless
associated with pulmonary embolism.

Physical Exam
Phlegmasia cerulea dolens Phlegmasia cerulea

dolens is an uncommon form of massive proximal (eg,

iliofemoral) venous thrombosis of the lower extremities
associated with a high degree of morbidity and mortality.
Signs and symptoms include sudden severe leg pain with

swelling, cyanosis, edema, venous gangrene,

compartment syndrome, and arterial compromise, often
followed by followed by circulatory collapse and shock.
Delay in treatment may result in death or loss of the
patient's limb.

Physical Exam
Screening for malignancy Since venous

thromboembolism may be the first manifestation of an

underlying malignancy, rectal examination and stool
testing for occult blood should be performed and
women should undergo a pelvic examination to rule out
the presence of a previously unsuspected pelvic mass or
malignancy. However, a routine exhaustive search for an
occult malignancy is neither warranted nor cost effective.

Laboratory Testing
The initial laboratory evaluation in patients with venous

thrombosis should include a complete blood count and

platelet count, coagulation studies (eg, prothrombin time,
activated partial thromboplastin time), renal function tests,
and urinalysis.
Consideration should be given to obtaining a prostate-

specific antigen measurement in men over the age of 50.

Any abnormality observed on initial testing should be
investigated aggressively.

Differential Diagnosis
When approaching the patient with suspected DVT of the lower

extremity, it is important to appreciate that only a minority of

patients (17 and 32 percent in two large series) actually have
the disease
Muscle strain, tear, or twisting injury to the leg 40 percent
Leg swelling in a paralyzed limb 9 percent
Lymphangitis or lymph obstruction 7 percent
Venous insufficiency 7 percent
Popliteal (Baker's) cyst 5 percent
Cellulitis 3 percent
Knee abnormality 2 percent
Unknown 26 percent

Diagnosis of DVT
A number of invasive and non-invasive approaches are possible (eg,

contrast venography, impedance plethysmography, compression

ultrasonography, D-dimer testing).
In most circumstances, compression ultrasonography is the

noninvasive approach of choice for the diagnosis of symptomatic

patients with a first episode of suspected DVT
A negative D-dimer assay may be insufficient to rule out DVT as a

stand-alone test in patient populations with a high prevalence of

venous thromboembolism, and not all D-dimer assays are validated
for this application. However, a D-dimer level <500 ng/mL by ELISA or
a negative SimpliRED assay in conjunction with a low clinical
probability (ie, Wells score) or other negative noninvasive tests may
be useful in excluding DVT, without the need for ultrasound testing.

Diagnosis of DVT
A positive noninvasive study in patients with a first episode of

DVT usually establishes the diagnosis, with a positive

predictive value for compression ultrasonography of 94 percent
(95% CI: 87-98 percent). If the initial study is negative and the
clinical suspicion of DVT is high, a repeat study should be
obtained on day 5 to 7.
Use of a single study via extended (complete) lower extremity

ultrasonography may obviate the need for repeat testing.

However, this technique requires specialized instrumentation
and is highly dependent on user expertise.
Venography is currently used only when noninvasive testing is

not clinically feasible or the results are equivocal.

Diagnosis of DVT
Pretest probability Ultrasonography and D-dimer

tests for DVT are most useful when the results are
combined with an assessment of pretest probability of
DVT. One report of 593 patients with suspected DVT
validated a measure of pretest probability (Wells score)
VT was documented in 3, 17, and 75 percent of patients

with low, moderate, or high pretest probabilities,

respectively.

Well Score
A review of 15 studies in which the Wells score was tested concluded

the following
Patients in the low pretest probability category had a median negative

predictive value for DVT of 96 percent (range: 87 to 100 percent),

indicating the usefulness of the Wells score for ruling out DVT.
The median negative predictive value for DVT in patients with a low

pretest probability was improved further by the presence of a negative

test for D-dimer (median value 99 percent, range: 96 to 100 percent).
Positive predictive values for DVT rarely exceeded 75 percent for

patients in the high pretest probability category, indicating that these

rules alone were not as useful for identifying patients who did have
thrombosis.

Screening for Hypercoagulable state

Inherited and acquired hypercoagulable states A

biologic risk factor for venous thrombosis can be identified

in over 60 percent of Caucasian patients under age 50
with a first idiopathic DVT. In addition, there is often more
than one factor at play in a given patient. As an example,
50 percent of thrombotic events in patients with inherited
thrombophilia are associated with an accompanying
acquired risk factor (eg, surgery, pregnancy, use of oral
contraceptives).
Some patients have more than one form of inherited

thrombophilia or may have combinations of inherited as

well as acquired thrombophilic states and are at even
greater risk for thrombosis.

Screening for Hypercoagulable state

A thrombophilic state leading to venous thrombosis can

be inherited or acquired:
Congenital/inherited (eg, factor V Leiden, protein C

deficiency)
Acquired (eg, following orthopedic surgery,
antiphospholipid antibody)
Associated with systemic disease (eg, malignancy)
Who to test There is currently no consensus regarding
who to test for inherited thrombophilia.

Screening for Hypercoagulable state

However, the likelihood of identifying an inherited thrombophilia

is increased several-fold by screening only patients with one or

more of the following:
Initial thrombosis occurring prior to age 50 without an

immediately identified risk factor (ie, idiopathic or unprovoked

venous thrombosis)
A family history of venous thromboembolism (ie, first-degree
relatives with VTE prior to age 50)
Recurrent venous thrombosis
Thrombosis occurring in unusual vascular beds such as portal,
hepatic, mesenteric, or cerebral veins
A history of warfarin-induced skin necrosis, which suggests
protein C deficiency.

Value of Screening
Value of screening Although we can identify patients at increased

risk for inherited thrombophilia, there is no clear clinical value to

screening for the following reasons:
Even if a hypercoagulable workup uncovers abnormalities

predisposing to VTE, the strongest risk factor for VTE recurrence is

the prior VTE event itself, particularly if idiopathic.
Patients with idiopathic VTE, whether or not they have an identifiable

inherited thrombophilia, are at high risk for recurrence (as high as 7 to

8 percent per year in some studies) after warfarin is discontinued, at
least for the first few years after the event.
Thus, the presence or absence of an inherited thrombophilia will

usually not change the decision regarding length of warfarin therapy.

Value of Screening
Screening information can be used to identify family

members with an inherited thrombophilia, but

anticoagulant prophylaxis is rarely recommended in
asymptomatic affected family members outside of high
risk situations.
Screening test interference A number of factors can

interfere with screening tests for thrombophilia (e.g. Acute

thrombosis, heparin, and coumadin therapies).
Therefore, it is generally best not to undertake testing at

the time of presentation with VTE.

Treatment for DVT

Rationale The primary objectives of treatment of DVT are to

prevent and/or treat the following complications:

Prevent further clot extension

Prevention of acute pulmonary embolism
Reducing the risk of recurrent thrombosis
Treatment of massive iliofemoral thrombosis with acute lower limb
ischemia and/or venous gangrene (ie, phlegmasia cerulea dolens)
Limiting the development of late complications, such as the postthrombotic syndrome, chronic venous insufficiency, and chronic
thromboembolic pulmonary hypertension.
Anticoagulant therapy is indicated for patients with symptomatic

proximal DVT, since pulmonary embolism will occur in approximately

50 percent of untreated individuals, most often within days or weeks
of the event.

Treatment for DVT

Initial therapy

The following recommendations for the treatment of acute venous thromboembolic

disease are in accord with the 2012 ACCP evidence-based clinical practice guidelines for antithrombotic and thrombolytic
therapy, as well as recommendations of the British Committee for Standards in Hematology, the joint guidelines of the
American College of Physicians and the American Academy of Family Physicians, and the American Heart
Association/American College of Cardiology.

Patients with DVT or pulmonary embolism should be

treated acutely with LMW heparin, fondaparinux,

unfractionated intravenous heparin, or adjusted-dose
subcutaneous heparin.
Dosing requirements for LMW heparin are different for

each LMW product. Minimal elements for early discharge

and/or outpatient therapy with LMW heparin or
fondaparinux are shown in the table.

Treatment of DVT
When unfractionated heparin is used, the dose should be

sufficient to prolong the activated partial thromboplastin

time (aPTT) to 1.5 to 2.5 times the mean of the control
value, or the upper limit of the normal aPTT range. A
survey of available weight-based nomograms supports
the view that they represent a safe and cost-effective
strategy for unfractionated heparin dosing in a number of
different health care settings.
Treatment with LMW heparin, fondaparinus, or

unfractionated heparin should be continued for at least

five days and oral anticoagulation should be overlapped
with LMW fondaparinux, or unfractionated heparin for at
least four to five days.

Treatment of DVT
For most patients, warfarin should be initiated

simultaneously with the heparin, at an initial oral dose of

approximately 5 mg/day. In elderly patients and in those at
high risk of bleeding or who are undernourished,
debilitated, or have heart failure or liver disease, the
starting dose should be reduced. The heparin product can
be discontinued on day five or six if the INR has been
therapeutic for two consecutive days.
For patients receiving unfractionated heparin (UFH),

ACCP Guidelines suggest that platelet counts be obtained

regularly to monitor for the development of
thrombocytopenia. The frequency and timing of such
counts depends upon the clinical situation.

Treatment of DVT
The heparin product should be stopped if any one of the

following occurs: a precipitous or sustained fall in the

platelet count, or a platelet count <100,000/microL.
The use of thrombolytic agents, surgical thrombectomy, or

percutaneous mechanical thrombectomy in the treatment

of venous thromboembolism must be individualized.
Patients with hemodynamically unstable PE or massive
iliofemoral thrombosis (ie, phlegmasia cerulea dolens),
and who are also at low risk to bleed, are the most
appropriate candidates for such treatment.

Treatment of DVT IVC filter

Inferior vena caval filter placement is recommended when

there is a contraindication to, or a failure of, anticoagulant

therapy in an individual with, or at high risk for, proximal
vein thrombosis or PE.
It is also recommended in patients with recurrent

thromboembolism despite adequate anticoagulation, for

chronic recurrent embolism with pulmonary hypertension,
and with the concurrent performance of surgical
pulmonary embolectomy or pulmonary
thromboendarterectomy.

Treatment of DVT
Oral anticoagulation with warfarin should prolong INR to a

target of 2.5 (range:2.0-3.0) If oral anticoagulants are

contraindicated or inconvenient, long-term therapy can be
undertaken with either dose-adjusted unfractionated heparin,
LMWH, or fondaparinux.
Because of ease of use, especially in the outpatient setting,

LMW heparin or fondaparinux is preferred to unfractionated

heparin.
There is insufficient information at the present time to

recommend the use of the newer oral anticoagulants (eg,

dabigatran, rivaroxaban, apixaban) for the treatment of DVT.

Duration of treatment
Duration of treatment The duration of anticoagulation

therapy varies with the clinical setting as well as with

patient values and preferences.
Patients with a first thromboembolic event in the context

of a reversible or time-limited risk factor (eg, trauma,

surgery) should be treated for three months.
Patients with a first idiopathic thromboembolic event

should be treated for a minimum of three months.

Following this, all patients should be evaluated for the
risk/benefit ratio of long-term therapy.

Duration of Treatment
Indefinite therapy is preferred in patients with a first

unprovoked episode of proximal DVT who have a greater

concern about recurrent VTE and a relatively lower
concern about the burdens of long-term anticoagulant
therapy.
In patients with a first isolated unprovoked or provoked
episode of distal DVT, three months of anticoagulant
therapy, rather than indefinite therapy, appears to be
sufficient.
Most patients with advanced malignancy should be
treated indefinitely or until the cancer resolves.

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